Anti-mycobacterium compositions and methods of preparing and using same

ABSTRACT

The present invention relates to compounds, compositions and methods for the prevention or treatment of mycobacterium infections. The compounds are naturally occurring and synthetic biflavonoids, flavonoids, chalcones and chalcone like compounds. The compounds were screened for anti-mycobacterium activity. Of the compounds showing anti-mycobacterium activity, eight were identified as particularly potent, exhibiting greater than 90% inhibition of the growth of Mtb at a concentration of 12.5 Πg/mL. The actual minimum inhibitory concentrations (MIC), defined as the lowest concentration inhibiting 99% of the inoculum, for the preferred compounds ranged from 6.8 to 48.3 ΠM.

[0001] This application is a continuation-in-part of provisionalapplication Ser. No. 60/155,519, filed Sep. 22, 1999.

FIELD OF THE INVENTION

[0002] The present invention relates to methods and compositions forpreventing or treating mycobacterium infections, particularlytuberculosis infections.

BACKGROUND OF THE INVENTION

[0003] Infectious diseases remain the largest cause of death in theworld today, greater than cardiovascular disease or cancer.¹ Amonginfectious diseases, tuberculosis (TB) is the leading cause of death.²

[0004] Tuberculosis, caused by the infection of Mycobacteriumtuberculosis (Mtb), kills three million people worldwide and eightmillion people develop the disease each year according to currentestimates by the World Health Organization (WHO). More people die fromTB than from malaria, diarrhea, AIDS and tropical diseases combined.

[0005] Tuberculosis mainly affects the lungs but can also involve otherorgans. TB strikes people of all ages, but is more common among theelderly. The disease can also afflict animals, especially livestock suchas cattle, hogs and poultry. This disease once ranked among the mostcommon causes of death in the world. Today, improved methods ofprevention, detection, diagnosis and treatment have greatly reduced boththe number of people who contract the disease and the number of peoplewho die from it. However, in the last decade, the outbreaks ofmultidrug-resistant tuberculosis (MDRTB) and TB amplified by the globalHIV pandemic make TB an urgent global issue.

[0006] One third of the world's population is infected with Mtb,³ afacultative intracellular bacillus. After infection with Mtb, thelifetime risk of developing TB is approximately 10%, while 90% ofinfected persons have latent infection with viable bacilli. This 10%rate of TB accounts for the 8 million persons reported annually withactive TB, and the resultant 3 million deaths. Moreover, TB is a seriousproblem faced by hemodialysis patients,⁴ and is the number one killer ofwomen of childbearing age around the world, with 1.2 million women dyingof the disease in 1997, according to reports by the WHO.⁵

[0007] TB infection is a serious problem for acquired immunodeficiencysyndrome (AIDS) patients. HIV-infected individuals are particularlysusceptible to infection with Mtb and the development of TB. Compared toan individual who is not infected with HIV, an individual infected withHIV has a 10 times greater risk of developing TB. In an individualinfected with HIV, the presence of other infections, including TB, mayallow HIV to multiply more quickly. This may result in more rapidprogression of HIV infection and AIDS.⁶ As HIV infection progresses,CD4+ lymphocytes decline in number and function. The immune system isless able to prevent the growth and local spread of Mtb. Even inHIV-infected patients, pulmonary TB (PTB) is still the most common formof TB. The presentation of the disease depends on the degree ofimmunosuppression. As in adults, the natural history of TB in a childinfected with HIV depends on the stage of HIV disease. Early in HIVinfection, when immunity is, strong, the signs of TB are similar tothose in a child without HIV infection. As HIV infection progresses andimmunity declines, dissemination of TB becomes more common andtuberculous meningitis, miliary tuberculosis, and widespread tuberculouslymphadenopathy occur more frequently.

[0008] HIV-positive patients and staff in health units face dailyexposure to TB. The risk of exposure is greatest in adult medical wardsand TB wards where there are many PTB cases. From 1990-1992, the Centersfor Disease Control (CDC) investigated outbreaks of MDRTB in severalhospitals and a state correctional system. Almost 300 cases of MDRTBwere identified in these outbreaks; most patients were HIV-seropositive.The mortality rate was 80%-90% and the median interval from diagnosis oftuberculosis to death ranged from 4-16 weeks.⁷ In 1995, about one thirdof the 17 million HIV-infected people worldwide were also co-infectedwith Mtb.⁶

[0009] Current treatment of TB requires taking at least two antibiotics,usually isoniazid and rifanipicin, supplemented with pyrazinamide andethambutol added when isoniazid resistance is suspected.

[0010] Isoniazid (isonicotinic acid hydrazide) (INH) was first reportedto be effective against Mtb and M bovis in 1952.⁸⁻¹⁰ Isoniazid, nowstill a front-line therapy against TB, has been shown to be an effectiveprophylactic antitubercular¹¹, and modern short-course chemotherapy isinitiated with three drugs: isoniazid, rifampin and pyrazinamide(PZA),often with the inclusion of a fourth drug, usually ethambutol. Recently,rifapentine, a derivative of rifamycin, was approved by the FDA for thetreatment of tuberculosis.¹²

[0011] The American Thoracic Society and the CDC in the United Statesnow recommend a treatment regimen of isoniazid, rifampin andpyrazinamide for 2 months, followed by isoniazid and rifampin for anadditional 4 months, as the standard 6-month regimen. Isoniazid, cheapand safe, has a wide therapeutic margin and high early bactericidalactivity so that it kills rapidly growing bacilli in lesions, but isinefficient in ultimately sterilizing these lesions. Rifampin and PZAare crucial in achieving sterilization by killing persistingsemi-dormant bacilli, and are thus responsible for shortening theduration of treatment from the earlier norm of 12-18 months to thecurrent standard of 6 months.¹³ However, many people fail to completethe lengthy therapy, treatment failures are high and MDR is increasing.A four-year study, led by the WHO, shows that of people who had beentreated for TB for less than a month, 36 percent harbored microbes thatresisted at least one of the four main anti-tuberculosis drugs.Moreover, 10% of infected people who had never been treated for thedisease carried a strain of Mtb that resisted at least one drug.¹⁴

[0012] Drug resistance resulting from inadequate treatment, such asirregular drug supply, inappropriate regimens or poor compliance is apotential threat to TB control programs throughout the world. Patientsinfected with strains resistant to multiple drugs are less likely to becured, particularly if they are infected with HIV or malnourished, andtheir treatment is more toxic and more expensive than the treatment ofpatients with susceptible organisms.

[0013] The resurgence of TB, the development of MDR to Mtb and thediscovery that the progression of TB is accelerated in HIV-positivepatients have intensified the need to develop more efficient drugs tocombat this disease.

BRIEF SUMMARY OF THE INVENTION

[0014] The present invention relates to compounds, compositions andmethods for treating and/or preventing mycobacterium infections,especially tuberculosis infections, in patients. The method is usefulfor treating or preventing mycobacterium infections in immunocomprisedpatients, particularly HIV infected patients.

[0015] The present invention relates to compounds, compositions andmethods for the prevention or treatment of mycobacterium infections. Thecompounds are naturally occurring and synthetic biflavonoids,flavonoids, chalcones and chalcone like compounds. The compounds werescreened for anti-mycobacterium activity and several were found to causeinhibition of a mycobacterium infection. Of these, eight were identifiedas particularly potent, exhibiting greater than 90% inhibition of thegrowth of Mtb at a concentration of 12.5 Πg/mL. The actual minimuminhibitory concentrations (MIC), defined as the lowest concentrationinhibiting 99% of the inoculum, for the preferred compounds ranged from6.8 to 48.3 ΠM.

[0016] Accordingly, one object of the invention is a method forpreventing or treating a mycobacterium infection in a mammal comprisingadministering to a mammal in need of anti-mycobacterium prevention ortreatment an effective anti-mycobacterium amount of at least onecompound of formula i.

[0017] wherein R₁-R₉ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁ wherein R₁₀ and R₁ independently comprise H alkyl(e.g., C₁₋₆ linear or branched alkyl) or aryl (e.g., unsubstitutedphenyl or phenyl substituted with one or more of the following: C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄ alkyl, hydroxyl, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈ alkyl, C₁₋₈ alkylamino-C₁₋₈alkyl, di(C₁₋₆ alkyl)amino-C₁₋₈ alkyl, nitro, azido or halogen); COR₁₂wherein R₁₂ comprises H, OH, O— alkyl (e.g., C₁₋₆ linear or branchedalkyl), O-aryl (e.g., unsubstituted phenyl or phenyl substituted withone or more of the following: C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄alkyl, hydroxyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈alkyl, C₁₋₈ alkylamino-C₁₋₈ alkyl, di(C₁₋₆ alkyl)amino-C₁₋₈ alkyl,nitro, azido or halogen) or amino; NHCOCH₃; O₂; OCOR₁₃ wherein R₁₃comprises alkyl (e.g., C₁₋₆ linear or branched alkyl) or aryl (e.g.,unsubstituted phenyl or phenyl substituted with one or more of thefollowing: C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄ alkyl, hydroxyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈ alkyl, C₁₋₈alkylamino-C₁₋₈ alkyl, di(C₁₋₆ alkyl)amino-C₁₋₈ alkyl, nitro, azido orhalogen); OAc; benzoyl; CONH₂; or NO₂; or a pharmaceutically acceptablederivative or salt thereof.

[0018] Compounds of the formula i as well as anti-mycobacteriumcompositions comprising compounds of the formula i are included withinthis aspect of the invention.

[0019] Another object of the invention is a method for preventing ortreating a mycobacterium infection in a mammal comprising administeringto a mammal in need of anti-mycobacterium prevention or treatment aneffective anti-mycobacterium amount of at least one compound of formulaii.

[0020] wherein R₁ comprises 4-fluorophenyl-, 3-hydroxyphenyl-,pyridin-3-yl-, furan-2yl-, phenanthren-2-yl-, 3-fluorenyl-,pyridin-2-yl-, naphthalen-1-yl-, pyridin-2-yl-,4-bromo-2-hydroxyphenyl-, pyridin-4-yl-, 2-hydroxy-4-methoxyphenyl-,4-aminophenyl-, pyridin-4-yl-, 2-hydroxy-5-methoxyphenyl-,4-methoxyphenyl-, 4-methoxyphenyl-, 2-hydroxy-5-chlorophenyl-,4-aminophenyl-, 3-hydroxynaphthalen-2-yl-, furan-2-yl- or pyridin-2-yl-;and

[0021] R₂ comprises pyridin-3-yl-, phenanthren-9-yl-, phenanthren-9-yl-,phenyl-, 2-aminopyridino-3-yl, 2-aminopyridino-3-yl-, pyridin-2-yl-,phenyl-, 4-dimethyl-aminophenyl-, furan-2-yl-, indol-2-yl-, furan-2-yl-,2-aminopyridin-3-yl-, 4-dimethylaminophenyl-, furan-2-yl-,pyridin-4-yl-, pyridin-3-yl-, 2-aminopyridin-3-yl-,2-aminopyridin-3-yl-, 2-aminopyridin-3-yl-, pyridin-4-yl- or4-methoxyphenyl-; or a pharmaceutically acceptable derivative or saltthereof.

[0022] Compounds of the formula ii as well as anti-mycobacteriumcompositions comprising compounds of the formula ii are included withinthis aspect of the invention.

[0023] Another object of the invention is a method for preventing ortreating a mycobacterium infection in a mammal comprising administeringto a mammal in need of anti-mycobacterium prevention or treatment aneffective anti-mycobacterium amount of at least one compound of formulaiii.

[0024] wherein R₁-R₈ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁ wherein R₁₀ and R₁₁ independently comprise H alkyl(e.g., C₁₋₆ linear or branched alkyl) or aryl (e.g., unsubstitutedphenyl or phenyl substituted with one or more of the following: C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄ alkyl, hydroxyl, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈ alkyl, C₁₋₈ alkylamino-C₁₋₈alkyl, di(C₁₋₆ alkyl)amino-C₁₋₈ alkyl, nitro, azido or halogen); COR₁₂wherein R₁₂ comprises H, OH, O— alkyl (e.g., C₁₋₆ linear or branchedalkyl), O-aryl (e.g., unsubstituted phenyl or phenyl substituted withone or more of the following: C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄alkyl, hydroxyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈alkyl, C₁₋₈ alkylamino-C₁₋₈alkyl, di(C₁₋₆ alkyl)amino-C₁₋₈ alkyl, nitro,azido or halogen) or amino; NHCOCH₃; O₂; OCOR₁₃ wherein R₁₃ comprisesalkyl (e.g., C₁₋₆ linear or branched alkyl) or aryl (e.g., unsubstitutedphenyl or phenyl substituted with one or more of the following: C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄ alkyl, hydroxyl, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈ alkyl, C₁₋₈ alkylamino-C₁₋₈alkyl, di(C₁₋₆ alkyl)amino-C₁₋₈ alkyl, nitro, azido or halogen); OAc;benzoyl; CONH₂; or NO₂; or pharmaceutically acceptable derivative orsalt thereof.

[0025] Compounds of the formula iii as well as anti-mycobacteriumcompositions comprising compounds of the formula iii are included withinthis aspect of the invention.

[0026] Another object of the invention is a method for preventing ortreating a mycobacterium infection in a mammal comprising administeringto a mammal in need of anti-mycobacterium prevention or treatment aneffective anti-mycobacterium amount of at least one compound of formulaiv.

[0027] wherein R—R₈ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁, wherein R₁₀ and R₁₁ independently comprise H alkyl(e.g., C₁₋₆ linear or branched alkyl) or aryl (e.g., unsubstitutedphenyl or phenyl substituted with one or more of the following: C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄ alkyl, hydroxyl, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈ alkyl, C₁₋₈ alkylamino-C₁₋₈alkyl, di(C₁₋₆ alkyl)amino-C₁₋₈ alkyl, nitro, azido or halogen); COR₁₂wherein R₁₂ comprises H, OH, O— alkyl (e.g., C₁₋₆ linear or branchedalkyl), O-aryl (e.g., unsubstituted phenyl or phenyl substituted withone or more of the following: C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄alkyl, hydroxyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈alkyl, C₁₋₈ alkylamino-C₁₋₈ alkyl, di(C₁₋₆ alkyl)amino-Cl 8 alkyl,nitro, azido or halogen) or amino; NHCOCH₃; O₂ ⁻; OCOR₁₃ wherein R₁₃comprises alkyl (e.g., C₁₋₆ linear or branched alkyl) or aryl (e.g.,unsubstituted phenyl or phenyl substituted with one or more of thefollowing: C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy-C₁₋₄ alkyl, hydroxyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, amino-C₁₋₈ alkyl, C₁₋₈alkylamino-C₁₋₈ alkyl, di(C₁₋₆ alkyl)amino-C₁₋₈ alkyl, nitro, azido orhalogen); OAc; benzoyl; CONH₂; or NO₂; or pharmaceutically acceptablederivative or salt thereof.

[0028] Compounds of the formula iv as well as anti-mycobacteriumcompositions comprising compounds of the formula iv are included withinthis aspect of the invention.

[0029] Yet another object of the invention is a method for treating orpreventing mycobacterium infection in a patient comprising biflavonoidcompounds, particularly 6-6″-biapigenin hexamethylether, volkensiflavonehexamethylether, GB-1a hexamethylether, 3′″-Nitro-C3-O-C4′″-biflavone,3′-8″-biflavone, 6-2′″-biflavone, 6-6″-binaringenin hexamethyl-ether or6-2′″-biapigenin or derivative or salt thereof and pharmaceuticallyacceptable carriers therefor.

[0030] Still yet another object of the invention is to provideanti-mycobacterium composition comprising biflavonoid compounds fortreating or preventing a mycobacterium infection in a patientparticularly 6-6″-biagpigenin hexamethylether, volkensiflavonehexamethylether, GB-1a hexamethylether, 3′″-Nitro-C3-O-C4′″-biflavone,3′-8″-biflavone, 6-2′″-biflavone, 6-6″-binaringenin hexamethylether or6-2′″-biapigenin or derivative or salt thereof and pharmaceuticallyacceptable carriers therefor.

[0031] These and other objects of the invention will be clear in lightof the detailed description below.

DETAILED DESCRIPTION OF THE INVENTION

[0032] This invention relates to compounds, compositions and methods fortreating or preventing mycobacterium infections in mammals. Thecompounds of the present invention are synthetic or naturally occurringchalcones, chalcone-like compounds, biflavonoids and flavonoids. Thecompounds were screened for anti-mycobacterium activity. Of thecompounds showing anti-mycobacterium activity, eight were identified asparticularly potent, exhibiting greater than 90% inhibition of thegrowth of Mtb at a concentration of 12.5 r/mL.

[0033] The preferred compounds of this invention, which exhibitedgreater than 90% inhibition of the growth Mtb at a concentration of12.5/mL, were chalcone-like compounds (heterocyclic ring substituted2-propen-1-one) 1-(4-fluorophenyl)-3-(pyridin-3-yl)-2-propen-1-one (53)(98%), 1-(3-hydroxyphenyl)-3-phenanthren-9-yl-2-prop en-1-one (54)(97%), 1-(5-pyridin-2-yl)-3-(phenanthen-9-yl)-2-propen-1-one (55) (96%),and 1-(furan-2-yl)-3-phenyl-2-propen-1-one (56) (96%); chalcones1-(2-hydroxyphenyl)-3-(3-chlorophenyl)-2-propen-1-one (24) (90%) and1-(2-hydroxyphenyl)-3-(3-iodophenyl)-2-propen-1-one (40) (92%); andbiflavonoids 6-6″-biapigenin hexamethylether (151) (96%), andvolkensiflavone hexamethylether (3-8″-naringenylapigeninhexamethylether) (152) (95%). The actual minimum inhibitoryconcentrations (MIC), defined as the lowest concentration inhibiting 99%of the inoculum, for 53, 54, 55, 56, 24, 40, and 151 were 6.8, 19.2,20.2, 31.5, 48.3, >35.7 and >20.1 ΠM, respectively. See Tables 1-5.

[0034] The compounds and compositions of the present invention can beused to treat or prevent mycobacterium infections. Representativemycobacterial organisms include Mycobacterium avium complex (MAC),Mycobacterium kansaii, Mycobacterium marinum, Mycobacterium phlei,Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium gordonae,Mycobacterium terrae complex, Mycobacterium haemophilum, Mycobacteriumfortuitum, Mycobacterium tuberculosis, Mycobacterium laprae,Mycobacterium scrofulaceum and Mycobacterium smegmatis. In practicingthis invention, the compounds and compositions are particularly usefulin treating Mycobacterium tuberculosis infections.

[0035] The compounds of the invention may be formulated as a solution oflyophilized powders for parenteral administration. Powders may bereconstituted by addition of a suitable diluent or otherpharmaceutically acceptable carrier prior to use. The liquid formulationis generally a buffered, isotonic, aqeuous solution. Examples ofsuitable diluents are normal isotonic saline solution, standard 5%dextrose in water or in buffered sodium or ammonium acetate solution.Such formulation is especially suitable for parenteral administration,but may also be used for oral administration. It may be desirable to addexcipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose,acacia, polyethylene glycol, mannitol, sodium choride or sodium citrate.

[0036] Alternatively, the compounds of the present invention may beencapsulated, tableted or prepared in an emulsion (oil-in-water orwater-in-oil) syrup for oral administration. Pharmaceutically acceptablesolids or liquid carriers, which are generally known in thepharmaceutical formulary arts, may be added to enhance or stabilize thecomposition, or to facilitate preparation of the composition. Solidcarriers include starch (corn or potato), lactose, calcium sulfatedihydrate, terra alba, croscarmellose sodium, magnesium stearate orstearic acid, talc, pectin, acacia, agar, gelatin, maltodextrins andmicrocrystalline cellulose, or colloidal silicon dioxide. Liquidcarriers include syrup, peanut oil, olive oil, corn oil, sesame oil,saline and water. The carrier may also include a sustained releasematerial such as glyceryl monostearate or glyceryl distearate, alone orwith a wax. The amount of solid carrier varies but, preferably, will bebetween about 10 mg to about 1 g per dosage unit.

[0037] The dosage ranges for administration of the compound s of theinvention are those necessary to produce the desired affect wherebysymptoms of infection are ameliorated. For example, as used herein, ananti-mycobacterium effective amount for treating or preventing amycobacterium infection refers to the amount administered so as tomaintain an amount which suppresses or inhibits mycobacterium infectionas evidenced by standard assay. The dosage will also be determined bythe existence of any adverse side effects that may accompany thecompounds. It is always desirable, whenever possible, to keep adverseside effects to a minimum.

[0038] One skilled in the art can easily determine the appropriatedosage, schedule, and method of administration for the exact formulationof the composition being used in order to achieve the desired effectiveconcentration in the individual patient. However, the dosage can varyfrom between about 0.001 mg/kg/day to about 50 mg/kg/day, but preferablybetween about 0.01 to about 1.0 mg/kg/day.

[0039] The following examples are illustrative of the invention but doesnot serve to limit its scope.

[0040] Experimental

[0041] General Experimental Procedures

[0042] Melting points were determined in open glass capillary tubes andare uncorrected.

[0043]¹H-NMR and ¹³C-NMR spectra were recorded on a Varian XL300 NMRspectrometer in CDCl₃, DMSO-d₆ or acetone-d₆ as specified using TMS asan internal standard. Chemical shifts are expressed in parts per million(r, ppm). IR spectra were recorded using a Midac FT-IR spectrometer,with samples being prepared as KBr pellets, or using a Perkin-Elmerspectrum 1000 FT-IR. Mass spectral data were recorded using a FinneganMAT 90 mass spectrometer. Analytical thin-layer chromatography (TLC) wascarried out on precoated plates (silica gel F₂₅₄ from EM Science).Column chromatography was performed with silica gel 60 (70-230 mesh fromEM Science). The structures of compounds were confirmed by their TLCprofiles as well as their IR, NMR and MS spectra.

EXAMPLE 1 Chalcones

[0044] (1,3-Diaryl-2-propen-1-ones) and Chalcone-Like Compounds(1,3-Diheterocyclic ring substituted 2-Propen-1-ones): Chalcones andchalcone-like compounds were prepared by base-catalyzed condensation ofappropriately substituted ketones with substituted benzaldehydes orheterocylic aldehydes (Scheme 1). To the mixture of the substitutedacetophenone and substituted benzaldehyde in alcohol was added a 60%solution of potassium hydroxide dropwise with stirring. The reactionmixture was kept at 0° C. for 2 days, then diluted with water andacidified with acetic acid. The precipitated chalcone was collected andrecrystalized from alcohol to yield pure chalcone.^(15,16)

[0045] 3-Chloro-2′-hydroxychalcone (24). M.p. 108-108.5 θC, APCIMS m/z257.3 [M-H]⁺ (relative intensity 100%), 259.2 [M−H+2]⁺ (isotope) (58%);IR (KBr) cm⁻¹: 3091, 3060, 3017 (aromatic CH, ═C—H), 3010-2800 (br,—O—H), 1647 (chalcone C═O), 1582, 1492 (arom.); ¹H-NMR Γ(CDCl₃)(ppm):12.710 (1H, s, OH-2′), 7.923 (1H, dd, J=8.1 Hz, 1.5 Hz, H-6′), 7.846(1H, d, J=15.6 Hz, H-E), 7.657 (1H, d, J=1.5 Hz, H-2), 7.651 (1H, d,J=15.6 Hz, H-Δ), 7.552-7.749 (2H, m, H-5′,6), 7.45-7.35 (2H, m, H-4,5),7.043 (1H, dd, J=8.1 Hz, 1.2 Hz, H-3′), and 6.967 (1H, ddd, J=8.1 Hz,6.9 Hz, 1.2 Hz, H-4′); ¹³C-NMR Γ(CDCl₃)(Ppm): 193.598 (>C═O), 163,792(═C<), 143.783 (═CH—), 136.756 (═CH—), 136.521 (═C<), 135.165 (═C<),130.784 (═CH—), 130.382 (═CH—), 129.760 (═CH—), 128.106 (═CH—), 127.119(═CH—), 121.521 (═CH—), 119.956 (═CH—), 119.03 (═C<), and 118.78 (═CH—).

[0046] 3-Iodo-2′-hydroxychalcone (MCR242, 40). APCIMS m/z 349.1 [M−H]⁺;IR (KBr) cm⁻¹: 3010-2800 (br, —O—H), 1638 (chalcone C═O), 1564, 1485(arom.); ¹H-NMR Γ(CDCl₃)(ppm): 12.712 (1H, s, OH-2′), 8.019 (1H, d,J=1.5 Hz, H-2), 7.923 (1H, dd, J=8.1 Hz, 1.5 Hz, H-6), 8.798 (1H, d,J=15.6 Hz, H-E), 7.756 (1H, dd, J=7.5 Hz, 1.5 Hz, H-6), 7.625 (1H, d,J=15.6 Hz, H-Δ), 7.603 (1H, dd, J=7.8 Hz, 1.2 Hz, H-6′), 7.519 (1H, t,d,J=7.8 Hz, 1.2 Hz, H5), 7.179 (1H, t, J=8.4 Hz, H-5′), 7.040 (1H, dd,J=7.2 Hz, 1.2 Hz, H-3′), 6.966 (1H, ddd, J=8.2 Hz, 7.2 Hz, 1.2 Hz,H-4′). ¹³C-NMR Γ(CDCl₃)(ppm): 193.578 (>C═O), 163.818 (>C═), 143.649(═CH—), 139.665 (═CH—), 137.070 (═CH—), 136.903 (>C═), 136.774 (═CH—),130.764 (═CH—), 129.816 (═CH—), 128.184 (═CH—), 121.431 (═CH—), 119.982(>C═), 119.056 (═CH—), 118.805 (═CH—), 94.880 (>C═).

[0047] 1-(4-Fluorophenyl)-3-(pyridin-3-yl)-2-propen-1-one (53)₃₂ M.p.126-127 θC, colorless crystals, APCIMS m/z 228.2 [M+H]⁺. ¹H-NMRΓ(CDCl₃)(ppm): 8.866 (1H, d, J=1.8 Hz, H-2), 8.638 (1H, dd, J=4.8 Hz,1.5 Hz,H-4), 8.0 (2H, ddd, J=9 Hz, 5.4 Hz, 2.1 Hz, H-2′,6′), 7.958 (1H,dt, J=8.1 Hz, 2.1 Hz, H-6), 7.805 (1H, d, J=15.9 Hz, H-E), 7.580 (1H, d,J=15.9 Hz, H-Δ), 7.380 (1H, dd, J=7.8 Hz, 4.8 Hz, H-5), 7.203 (ddd,H=9.0 Hz, 8.1 Hz, 2.1 Hz, H-3′,5′). ¹³C-NMR Γ(CDCl₃)(Ppm): 188.321(═C<), 167.628 (═C<), 164.236 (═C<), 151.314 (═CH—), 150.061 (═CH—),141.252 (═CH—), 134.726 (═CH—), 134.180 (═C<), 131.319 (═CH—), 131.198(═CH—), 130.638 (═C<), 123.867 (═CH—), 123.435 (═CH—), 116.105 (═CH—),115.817 (═CH—).

[0048] 1-(3-Hydroxyphenyl)-3-phenanthren-9-yl-2-propen-1-one (54). M.p.212-213θC, colorless crystals, APCIMS m/z 325.1 [M+H]⁺. ¹H-NMRΓ(Acetone-d₆)(ppm): 8.926 (1H, m, H-8), 8.86 (1H, d, J=8.1 Hz, H-5),8.781 (bs, OH), 8.643 (1H, d, J=15.6 Hz, H-E), 8.478 (1H, s, H-10),8.360 (1H, m, H-4), 8.09 (1H, dd, J=7.8 Hz, 1.8 Hz, H-1), 7.964 (1H, d,J=15.5 Hz, H-Δ), 7.818-7.643 (6H, m, H-2,3,6,7,2′,6′), 7.442 (1H, t,J=7.8 Hz, H-5′), 7.167 (1H, dt, J=7.2 Hz, H-4′). ¹³C-NMRΓ(Acetone-d₆)(ppm): 190.016 (>C═O), 158.956 (═C<), 140.729 ((═C<),141.905 (═CH—), 132.465 (═C<), 132.276 (═C<), 132.207 (═C<), 13.1.562(═C<), 131.373 (═C<), 130.910 (═CH—), 130.432 (═CH—), 128.944 (═CH—),128.383 (═CH—), 128.163 (═CH—), 128.231 (═CH—), 127.768 (═CH—), 126.425(═CH—), 125.226 (═CH═), 124.467 (═CH—), 123.799 (═CH—), 121.143 (═CH—),121.022 (═CH—), and 115.892 (═CH—).

[0049] 1-(Furan-2-yl)-3-phenyl-2-propen-1-one (MCR211, 56).³³ M.p.94-95θC, colorless crystals, APCIMS m/z 199.1 [M+H]⁺. ¹H-NMRΓ(CDCl₃)(Ppm): 7.890 (1H, d, J=15.9 Hz, H—), 7.661 (1H, dd, J=1.5 Hz,0.9 Hz, H-5′). 7.659 (2H, m, H-2,6), 7.46 (1H, d, J=15.6 Hz, H—), 7.421(3H, m, H-3,4,5), 7.341 (1H, dd, J=3.3 Hz, 0.9 Hz, H-3′), 6.603 (1H, dd,J=3.6 Hz, 1.5 Hz, H-4′). ¹³C-NMR Γ(CDCl₃)(ppm): 178.195 (>C═O), 153.822(═C<, C-2′), 146.636 (═CH—, C-5′), 144.101 (C—), 134.814 (═C<, C-1),130.686 (═CH—, C-4), 129.016 (═CH—, C-3,5), 128.607 (═CH—, C-2,6),121.216 (═CH—, C-4′), 117.566 (═CH—, C—), 112.596 (═CH—, C-3′).

EXAMPLE 2 Flavones

[0050] Flavones were synthesized by treating the correspondingchalcones, prepared by the method described above, with selenium dioxidein amyl alcohol. Thus, 2′-, 3′- and 4′-monohalogenoflavones wereprepared as usual by condensation of hydroxyacetophenone with o-, m- andp-halogenobenzaldehydes to provide chalcones. This was followed bycyclization of the chalcones with selenium dioxide in amyl alcohol.¹⁷⁻¹⁹6-Fluoro-, 6-chloro- and 6-bromoflavones and related compounds wereprepared from 2-hydroxy-5-halogenoacetophenones.¹⁹

EXAMPLE 3 Flavonols

[0051] Flavonols were prepared by treating the corresponding chalconeswith a 16% solution of aqueous sodium hydroxide and a 15% solution ofhydrogen peroxide (v/v 1:1). The 6-halogenoflavonols were prepared ingood yield by cyclization of the corresponding chalcones in coldalkaline hydrogen peroxide.²⁰⁻²¹

EXAMPLE 4 Flavanones

[0052] Flavanones were prepared by refluxing the corresponding chalconeswith phosphoric acid in alcohol for 2-3 days. Generally,2-hydroxy-5-halogenoacetophenones condensed smoothly with benzaldehydeor p-anisaldehyde in the presence of alcoholic alkali, giving chalcones,which were cyclized in phosphoric acid to obtain 6-halogenoflavanones.²²

[0053] 5-Methoxy-8-bromo-flavanone (MCR264, 133). M.p. 134-165 θC,colorless crystals, APCIMS m/z 333.1 [M]⁺ (relative intensity 100%),335.0 [M+2]⁺ (94%); ¹H-NMR Γ(CDCl₃)(ppm): 7.656 (1H, d, J=8.7 Hz, H-6),7.511 (2H, dt, J=7.5 Hz, 1.8 Hz, H-2′,6′), 7.526-7.360 (5H, m, B-ringprotons), 6.495 (1H, d, J=9.0 Hz, H-7), 5.572 (1H, m, H-2), 3.030 (2H,m, H-3A and H-3L). ¹³C-NMR Γ(CDCl₃)(ppm): 190.132 (>C═O), 160.211 (═C<),158.959 (═C<), 138.964 (═CH—), 138.296 (═C<), 128.887 (═CH—), 128.652(═CH—), 125.844 (═CH—), 112.474 (═C<), 105.326 (═CH—), 102.534 (═C<),78.034 (═CH—, C-2), 58.353 (—CH₃, 5-OCH₃), and 45.297 (>CH₂, 3-C).

EXAMPLE 5 Biflavonoids

[0054] Naturally occurring biflavanoids amentoflavone, agathisflavone,robustaflavone, hinokflavone, rhusflavanone, succedaneaflavanone,volkensiflavone, morelloflavone and GB-1a were isolated from Rhussuccedanea and Garcinia multiflora. ²³⁻²⁵ Synthetic C—C linkagebiflavonoids were synthesized by Ulman condensation ofmonohalogenoflavones.^(17c,29,30) Hexa-O-methyl-8,8″-binaringenin wasobtained from acidic cyclization of the corresponding bichalcone, whichwas prepared by Friedel-Crafts reaction of2,2′,4,4′,6,6′-hexamethoxybiphenyl with acetic anhydride and anhydrousaluminum chloride in nitrobenzene by refluxing with alcoholic H₃PO₄ fortwo weeks.³¹

[0055] 6,6″-Biapigenin hexamethylether (MCR 408, 151). 6,6″-Biapigeninhexamethylether (151) was synthesized by a three-step synthesis from4,4′-dibenzyloxy-2,2′,6,6′-tetramethoxybiphenyl, which was prepared fromthe Ullmann reaction of benzyl 4-iodo-3,5-dimethoxyphenylether.³⁴ Hoeschreaction on 4,4′-dibenzyloxy-2,2′,6′6′-tetramethoxybiphenyl with CH₃CN,ZnCl₂ and HCl in dry CHCl₃-Et₂O (1:1) yielded the key product,4,4′-dihydroxy3,3′-diacetyl-2,2′,6′6′-tetramethoxybiphenyl, followed bytreatment with two moles of p-anisaldehyde in the presence of alkali toafford the bichalcone. Oxidative cyclization of the bichalcone with SeO₂in dioxane followed by preparative TLC afforded 6,6″-biapigeninhexamethylether, m.p. 303-304 θC, colorless crystals, APCIMS m/z 623.3[M+H]⁺;

[0056]¹H-NMR Γ(CDCl₃)(ppm): 7.862 (4H, d, J=9.3 Hz, H-2′,6′,2′″,6′″),7.454 (2H, s, H-8, 8″), 7.026 (4H, J=8.4 Hz, H-3′,5′,3′″,5′″), 6.781(2H, s, H-3,3″), 4.344 (6H, s, 5,5″-OCH₃) and 3.899 (12H, s,7,7″,4′,4′″-OCH₃).

[0057]Volkensiflavone hexamethylether (MCR360, 152). Volkensiflavonehexamethylether was prepared from volkensiflavone, which was isolatedfrom the methanol extract of Garcinia muhiflora. ²⁸

[0058] Isolation of volkensiflavone: The dried heartwood of Garciniamultiflora (shavings, 3 kg) was extracted with boiling methanol (4times). The extract was evaporated to yield a brown oily material, whichwas extracted with toluene to remove oily substances. The insoluble partwas extracted with ethyl acetate. The ethyl acetate extract yielded alight brown solid (25 g) which was chromatographed on 500 g of silicagel, eluting with toluene-ethyl acetate (1:2) to provide fractions I (4g), II (0.3 g) and III (1.7 g). Fraction I was further chromatographedon a column of polyamide (nylon 66, 200 g), eluting with 70% aqueousmethanol to provide fractions 1a (0.1 g), 1b (0.6 g), 1c (0.35 g) and 1d(0.5 g). Recrystallization of fraction 1d with ethyl acetate/methanolyielded 0.3 g of volkensiflavone as a yellow powder.

[0059] Methylation of volkensiflavone: 200 mg of volkensiflavone wasdissolved in 20 mL of dry acetone and 2.5 mL of dimethylsulfate and 2 gof potassium carbonate were added. The solution was refluxed for 4 hr,and then filtered. The filtrate was concentrated and purified by silicagel column chromatography using a mixture of toluene and ethyl acetatein a ratio of 1:2 as the eluting solvent. Fractions containingvolkensiflavone hexamethylether were combined and concentrated to leavean ivory solid which was recrystallized from a solvent mixture ofchloroform and methanol to obtain volkensiflavone hexamethylether ascolorless crystals, 138 mg, m.p. 258-260 θC, EIMS m/z 624 [M]⁺, IR (KBr)cm⁻¹: 2900, 2950, 2850 (OMe), 1680 (flavanone>CO), 1645 (flavone>CO),1600, 1580, 1510, 1490 (arom.); ¹H-NMR Γ(CDCl₃)(ppm): 7.70 (2H, d, J=9Hz, H-2′″,6′″), 7.13 (2H, J=9 Hz, H-2′,6′), 6.87 (2H, d, J=9 Hz, H-3′″,5′″), 6.63 (2H, d, J=9 Hz, H-3′,5′), 6.50 (1H, s, H-3″), 6.30 (1H, d,J=2 Hz, H-8), 6.23 (1H, s, H-6″), 6.20 (1H, d, J=2 Hz, H-6), 5.80 (1H,d, J=12 Hz, H-2-H), 4.90 (1H, d, J=12 Hz, H-3), six methoxyl groups at3.93 (3H, s), 3.87 (3H, s), 3.83 (6H, s), 3.77 (3H, s), 3.67 (3H, s).

EXAMPLE 6 In Vitro Evaluation of Anti-tuberculosis Activity³⁵⁻³⁸

[0060] The screening was conducted at a drug concentration of 12.5 Πg/mLagainst Mtb H38Rv in BACTEC 12B medium using a BACTEC 460 radiometricsystem. The assay procedure was carried out according to the methoddescribed previously.³⁹ Compounds were solubilized in dimethylsulfoxideat 1 mg/mL and sterilized by passage through 0.22 Γm PFTE filters. Avolume of 50 FL was added to 4 mL BACTEC 12B medium (Becton Dickinson)to achieve a final concentration of 12.5 Πg/mL. Approximately 4×10⁵colony forming units of M. tuberculosis H37Rv (ATCC 27294) were addedand the cultures were incubated at 37 θC. Starting on the second day ofincubation, the Growth Index (GI, 1 GI unit=0.0025 dpm ¹⁴CO₂) wasdetermined daily until the controls (drug-free) achieved a GI of 999.The percent inhibition was calculated as 1—(test sample GI÷controlGI)×100. The test compounds and results are summarized in Tables 1-5.

[0061] Among 179 compounds screened, eight compounds, includingbiflavonoids, chalcones and chalcone-like compounds, demonstrated>90%inhibition against Mtb H37Rv at a drug concentration of 12.5 Πg/mL.Forty-one compounds exhibited activity between 50-89% (80-89%: eightcompounds; 70-79%: seven compounds; 60-69%: fourteen compounds; 50-59%:twelve compounds). And seventy-three compounds displayed activity lessthan 50% (40-49%: fifteen compounds; 30-39%: six compounds; 20-29%:eighteen compounds; 10-19%: sixteen compounds; 1-9%: eighteencompounds). The remaining forty-eight compounds were inactive againstMtb H37RV under the test conditions described above.

[0062] Chalcones (1,3-Diaryl-2-propen-1-ones)

[0063] The results of anti-TB screening of chalcones are displayed inTable 1. Chalcones with a 2-hydroxyl group in the A ring and a 3-iodo or3-chloro group in the B ring (40 and 24, respectively) demonstrated thestrongest activity among this series of compounds (92% and 90%inhibition against Mtb at a drug concentration of 12.5 Πg/mL,respectively). Chalcones without halogen substitution in the moleculeexhibited less activity compared to those with a halogen substitution.Introducing a methoxyl group at the 4′-position of compound 40 to derivecompound 43 resulted in a dramatic decrease in activity [43 (47%)compared to 40 (92%)].

[0064] The activity of 2′-hydroxychalcone (61% inhibition) was enhancedby introducing a chloro or a methoxyl group at the 4′-position of theA-ring, e.g. compound 25 (89%), and 1 (78%), while a bromo, or a iodosubstituent at the 4′-position of the B-ring led to a decrease inactivity, e.g. 35 (57%) and 21 (45%). The effect of a substituent at the4′-position of the A-ring of 2′-hydroxy chalcone for anti-TB activitywas Cl [25 (89%)]>OCH₃ [1 (78%)]>no substituent [5 (61%)]>Br [35(57%)]>I [21 (45%)]. The bromo substitution at the 3′-position of theA-ring of 2′-hydroxychalcone slightly increased the activity [32 (79%)vs. 5 (61%)]. The effect of substituent at the 5′-position of the A-ringof 2′-hydroxychalcone was Br [34 (68%)] # phenyl [3 (68%)] # Cl [26(67%)]>H [5 (61%)]>I [42 (51%)]>NH₂[12 (6%)]. The effect of asubstitution of a halogen group at a different position of the A-ring of2′-hydroxychalcone was 4′-[25 (89%)]>5′-[26 (67%)] for chlorosubstituents, 3′-[32 (79%)]>5′-[34 (68%)]>4′-[35 (57%)] for bromosubstituents and 5′-[42 (52%)]>4′-[45 (21%)]>3′-[47 (0%)] for iodosubstituents. Introducing an additional substituent on either the A- orB-ring of the above 2′-hydroxychalcones resulted in decreasing orabolishing the activity, e.g. 25 (89%) vs. 28 (57%), 1 (78%) vs. 7(40%), 34 (68%) vs. 37 (23%) and 38 (8%), 26 (67%) vs. 29 (20%), 35(57%) vs. 36 (25%) and 38 (12%), 42 (51%) vs. 48 (0%) and 47 (0%) vs. 49(0%).

[0065] The substitution of a halogen group on the B-ring of2′-hydroxychalcone led to an increase in the anti-TB activity. Compoundswith a halogen substituent at the 3-position demonstrated strongeractivity than those with a substituent of a halogen at the 2-position or4-position, such as 40 (92%), 44 (41%) and 46 (21%) for 3-, 2- and4-iodo substitution, respectively; 31 (83%) and 33 (70%) for 2- and4-bromo substitution, respectively; 24 (90%) and 27 (67%) for 3- and4-chloro substitution, respectively. Introducing an additionalsubstituent, such as a methoxyl, bromo or carboxyl group on the A-ringof 2′-hydroxy-3-iodochalcone (40) led to a dramatic decrease or completeloss of activity, e.g. 43 (47%), 50 (0%) and 51 (0%) for 4′-methoxy-,5′-carboxyl- and 3′-bromo-2′-hydroxy-3-iodochalcone, respectively.

[0066] Substitution of a 2′-hydroxyl group in 2′-hydroxy-2-iodochalcone[44 (41%)] with an amino group at the 3′-position dramatically increasedthe activity [41 (88%)].

[0067] Chalcone-Like Compounds (1,3-disubstituted 2-propen-1-ones)

[0068] Chalcone-like compounds demonstrated the most significant anti-TBactivity among all the compounds evaluated, including chalcones,flavonoids and biflavonoids. As presented in Table 2, compounds 53, 54,55, and 56 inhibited 98%, 97%, 96% and 96% growth of Mtb H37Rv at a drugconcentration of 12.5 Πg/mL, respectively. The common structural featureof these four compounds is that they all have a heterocyclic ring or aphenyl ring with a hydrophilic group substituent on one side of themolecule, and an aromatic ring, such as phenyl or phenanthrenyl, with orwithout a hydrophobic substituent on the other side. Additionalhydrophylic substituents, such as methoxyl, hydroxyl and amino groupsresulted in dramatic decrease or complete loss of activity. From theabove results, active compounds resulted from structures having alipophilic group on one side and a hydrophilic group on the other sideof the 2-propen-1-one core template.

[0069] Flavones

[0070] The anti-TB activities of flavones are presented in Table 3. Allflavones tested, including carboxylated, halogenated, hydroxylated andmethoxylated flavones were only moderately to weakly active or inactive,while halogenated flavones or halogenated flavonols (3-hydroxyflavones)demonstrated moderate activity. Flavones with bromine or chlorinesubstitution at the 8-position displayed inhibitory activity against Mtbwith 66% and 62% growth inhibition at a dose of 12.5 Πg/mL,respectively, while the flavones with a halogen substitution at the3-position (compound 127), 6-, 7-, or 8-position of ring A (compounds102, 105, 106, 112, 114, 122, 123 and 124) and 2′, 3′, or 4′-position ofring B (compounds 84, 97, 99, 100, 101, 111 and 121) were weakly activeor inactive. Flavonol (3-hydroxyflavone) (92) exhibited weak activity of38% inhibition. The substitution of a methoxyl group at the 4′-positionof flavonol (88) led to a small increase in activity (10% increasecompared to 92). Further substitution of a 6-Cl or a 7-F-group on4′-methoxyflavonol (87 and 85) did not change the activity. However, asubstitution of an iodo group at the 7 or 8-position, or a fluoro or abromo group at the 6-position or a carboxyl group at the 6-position of4′-methoxyflavonol resulted in significant decreases in, or completeloss of, activity.

[0071] Flavanones

[0072] Eighteen flavanones were evaluated for anti-TB activity. Theresults are listed in Table 4. 5-Methoxy-8-bromoflavanone (133)demonstrated the most significant activity among these flavanones, with87% inhibition against Mtb. The substitution of a bromo group on theB-ring demonstrated higher activity than that on the A-ring[3′-bromo-(134), 73%, versus 7-bromo-flavanone (136), 53%].

[0073] Biflavonoids

[0074] The results of anti-TB activity of biflavonoids are presented inTable 5. Methoxylated biflavonoids 6,6″-biapigenin hexamethylether(151), volkensiflavone hexamethylether (152) and GB-1a hexamethylether(153) demonstrated strong inhibitory activity against Mtb with 96%, 95%and 87% growth inhibition at a concentration of 12.5 Πg/mL,respectively. These biflavonoids were composed of two apigenin unitsthrough a I6-II6 linkage, one naringenin and one apigenin unit or twonarigenin units with thea linkage at the I3-II8 position (3-position ofunit I linked to 8-position of unit II) (152 and 153).

[0075] Biflavonoid methylethers constructed with two flavone units orwith a flavone and a flavanone unit displayed equal strength of activity(151 and 152). A biflavonoid methylether (153) constructed with twoflavanone units demonstrated less activity than that constructed with aflavone and a flavanone (152) (87% versus 95% inhibition), although bothcompounds have the same linkage structure (I3-II8). Biapigeninhexamethylether with a linkage of I3-II3 (159) was completely devoid ofactivity. This result indicated that the I6-II6 linkage might beimportant for the activity. Comparison of the inactive binaringeninhexamethylether constructed by two units of naringenin trimethyletherthrough a linkage (157) to the active compounds 151 and 153, it was

[0076] observed that two units of the flavone structure were necessaryfor the activity of biflavonoids with a I6-II6 linkage and I3-II8linkage was important for the activity of biflavonoids composed of aflavanone and a flavone unit. Hydroxylated biflavonoids, biflavonoidglucosides or unsubstituted biflavonoids were inactive with theexception that I3′-II8″-biflavone (155) exhibited moderate activity.This result indicated that the lipophilic property of a compound mightbe important for the activity.

[0077] In conclusion, two chalcone compounds (24 and 40) and fourchalone like compounds (heterocyclic ring substituted 2-propen-1-ones)(53, 54, 55 and 56) exhibited greater than 90 percent inhibition againstMtb. The common structural features of these six compounds are that allthe compounds have two aromatic rings, one ring substituted with aheteroatom and the other with or without hydrophobic substitutions.Introduction of extra hydrophilic substituents such as methoxyl,hydroxyl and amino groups would render the compounds less active. Withthe exception of compound 53, the other five compounds all have ahydrogen-bonding group substituted on the A-ring, while the B-ringremained hydrophobic. Structural superposition analysis indicateed thatcompound 53 can actually be superimposed on the other five compounds theother way. For example, compound 53 can superimpose its A-ring with theB-ring of compound 56, while keeping its B ring superimposed with the Aring of compound 56 (Scheme 2).

[0078] Flavones and flavanones can be viewed as geometricallyconstrained chalcone analogues. It may indeed be due to these structuralconstraints that they are less active compared to chalcones. Someexamples illustrate the relationship of activity between a chalcone andits corresponding flavone, i.e., when a chalcone was converted to itscorresponding flavone, the anti-TB activity decreased. Examples of thisinclude compound 44 being converted to compound 100 in which activitydecreased from 41% to 22%; 44 to 100, 41% to 22%; 31 to 99, 83% to 23%;33 to 97, 70% to 26%, 24 to 121, 90% to 0%; and 27 to 111, 67% to 7%.The only exception to this pattern was compound 46 being converted tocompound 84 (21% to 51%).

[0079] Compared to flavanones, flavones are less active, and arestructurally more restricted, with the two terminal aromatic rings inthe same plane. The structures of the biflavonoids are apparentlydifferent from that of chalcone and flavanoid monomers. The two activebiflavonoids have only methoxyl substitutions (a methoxyl group is not agood hydrogen bonding group), while the chalcone and chalcone-likecompounds prefer a hydroxyl or other hydrogen bonding group. Withoutbeing bound by any theory of operation for this invention, mostprobably, the biflavonoids kill Mtb by a different mechanism. TABLE 1Anti-tuberculosis Activity of Chalcones

Activity A- ring B- ring % inhibition Compds 2′- 3′- 4′- 5′- 6′- 2- 3-4- 5- at 12.5 πg/mL 1 MCR206 OH OCH₃ 78 2 MCR202 OH OCH₃ OCH₃ 75 3MCR251 OH phenyl 68 4 MCR388 NO₂ OCH₃ 62 5 MCR201 OH 61 6 MCR222 OH OCH₂⁻ O⁻ 53 7 MCR205 OH OCH₃ OCH₃ OCH₃ 40 8 MCR208 OH OCH₃ 39 9 MCR209 OHOCH₃ OCH₃ 32 10 MCR210 OH OH 18 11 MCR255 OH NH₂ 11 12 MCR256 OH NH₂ 613 MCR385 NH₂ 5 14 MCR203 OH EtO EtO 0 15 MCR207 OH OCH₃ OH OCH₃ OCH₃OCH₃ 0 16 MCR250 OH COOH OCH₃ 0 17 MCR253 OH NHCOCH₃ 0 20 MCR216 F OCH₃82 21 MCR214 OH F OCH₃ 66 22 MCR217 OH F OCH₃ 63 23 MCR215 OH F OCH₃ 4524 MCR224 OH Cl 90 25 MCR226 OH Cl 89 26 MCR228 OH Cl 67 27 MCR223 OH Cl67 28 MCR225 OH Cl OCH₃ 57 29 MCR227 OH Cl OCH₃ 20 30 MCR343 OH Cl NA 31MCR234 OH Br 83 32 MCR235 OH Br 79 33 MCR230 OH Br 70 34 MCR233 OH Br 6835 MCR232 OH Br 57 36 MCR236 OH Br OCH₃ 25 37 MCR237 OH Br OCH₃ 23 38MCR345 OH Br NH₂ 12 39 MCR346 OH Br NH₂ 8 40 MCR242 OH I 92 41 MCR347NH₂ I 88 42 MCR218 OH I 51 43 MCR246 OH OCH₃ I 47 44 MCR244 OH I 41 45MCR240 OH I 21 46 MCR245 OH I 21 47 MCR239 OH I 0 48 MCR243 OH I OCH₃ 049 MCR248 OH I OCH₃ 0 50 MCR238 OH COOH I 0

[0080] TABLE 2 Anti-Tuberculosis Activity of Chalcone-like Compounds

Activity % inhibition Com- at 12.5 pounds R R′ πg/mL 53 4-fluorophenyl-pyridin-3-yl- 98 MCR340 54 3-hydroxyphenyl- phenanthren-9-yl- 97 MCR34955 pyridin-3-yl- phenanthren-9-yl- 96 MCR350 56 furan-2-yl- phenyl- 96MCR211 57 phenanthren-2-yl- 2-amino- 74 MCR383 pyridino-3-yl- 593-fluorenyl- 2-amino- 53 MCR382 pyridino-3-yl- 60 pyridin-2-yl-pyridin-2-yl- 42 MCR390 61 naphthalen-1-yl- phenyl- 37 MCR252 62pyridin-2-yl- 4-dimethyl- 16 MCR391 aminophenyl- 63 4-bromo-2-hydroxy-furan-2-yl- 17 MCR221 phenyl- 64 pyridin-2-yl- indol-2-yl- 12 MCR348 652-hydroxy-4-methoxy- furan-2-yl- 3 MCR212 phenyl- 66 4-aminophenyl-2-amino- 7 MCR379 pyridin-3-yl- 68 pyridin-4-yl- 4-dimethyl- 1 MCR392aminophenyl- 69 2-hydroxy-5-methoxy- furan-2-yl- 0 MCR213 phenyl- 704-methoxyphenyl- pyridin-4-yl- 0 MCR338 71 4-methoxyphenyl-pyridin-3-yl- 0 MCR339 72 2-hydroxy-5-chloro- 2-amino- 0 MCR341 phenyl-pyridin-3-yl- 73 4-aminophenyl- 2-amino- 0 MCR380 pyridin-3-yl- 743-hydroxy- 2-amino- 0 MCR381 naphthalen-2-yl- pyridin-3-yl- 75furan-2-yl- pyridin-4-yl- 0 MCR386 76 pyridin-2-yl- 4-methoxyphenyl- 0MCR389

[0081] TABLE 3 Anti-tuberculosis Activity of Flavones

Activity % Inhibition Compds 3 5 6 7 8 2′ 3′ 4′ 5′ at 12.5 πg/mL 77MCR293 Br 66 78 MCR288 Cl 62 79 MCR329 OH I 64 80 MCR322 OH Br 60 81MCR317 OH Cl 58 82 MCR319 OH Br 58 84 MCR303 I 51 85 MCR312 OH F OCH₃ 5086 MCR314 OAc F OCH₃ 50 87 MCR316 OH Cl OCH₃ 48 88 MCR332 OH OCH₃ 48 89MCR323 OCH₃ Br 44 90 MCR315 OH F 43 91 MCR328 OH I OCH₃ 43 92 MCR309 OH38 93 MCR275 OCH₃ 29 94 MCR311 OH F OCH₃ 29 95 MCR306 NO₂ Cl 28 96MCR324 Br OCH₃ 28 97 MCR290 Br 26 98 MCR320 OH Br OCH₃ 24 99 MCR289 Br23 100 MCR295 I 22 101 MCR304 I 22 102 MCR297 I 20 103 MCR298 Br OCH₃ Cl19 104 MCR276 OH 18 105 MCR283 F 15 106 MCR292 Br 15 107 MCR305 I OCH₃15 108 MCR294 Br 13 109 MCR277 OCH₃ OCH₃ OCH₃ 12 110 MCR308 benzoylbenzoyl 12 111 MCR284 Cl 7 112 MCR282 F 7 113 MCR330 OH I OCH₃ 6 114MCR296 I 5 115 MCR307 COOH OCH₃ 2 116 MCR278 OH 1 117 MCR274 OCH₃ 0 118MCR280 F OCH₃ 0 119 MCR279 OCH₃ OCH₃ 0 120 MCR281 F OCH₃ 0 121 MCR285 Cl0 122 MCR287 Cl 0 123 MCR291 Br 0 124 MCR298 I 0 125 MCR299 OCH₃ OCH₃ IOCH₃ 0 126 MCR299 OCH₃ OCH₃ I OCH₃ 0 127 MCR301 I 0 128 MCR302 I OCH₃ 0130 MCR331 OH COOH OCH₃ 0 131 MCR394 Br OCH₃ OCH₃ OCH₃ 0 132 MCR273 OCH₃OCH₃ OH 0

[0082] TABLE 4 Anti-tuberculosis Activity of Flavanones

Activity % Inhibition Compounds 3 5 6 7 8 3′ 4′ 5′ at 12.5 πg/mL 133MCR264 OCH₃ Br 87 134 MCR266 Br 73 135 MCR333 OH Cl 63 136 MCR263 Br 53137 MCR261 OCH₃ Cl 48 138 MCR260 Cl 30 139 MCR267 I 27 140 MCR265 Br₂OCH₃ OCH₃ OCH₃ OCH₃ OCH₃ 16 141 MCR268 I 9 142 MCR262 Br 8 143 MCR259 F7 144 MCR258 OCH₃ OCH₃ OCH₃ OCH₃ OCH₃ 0 145 MCR271 COOH OCH₃ 0 146MCR270 COOH 0 147 MCR272 OCH₃ NO₂ 0 148 MCR335 Br₂ 0 149 MCR269 I OCH₃ 0

[0083] TABLE 5 Anti-tuberculosis Activity of Biflavonoids Activity %Inhibition Compds Name units Linkage at 12.5 Πg/mL 151 MCR 4086-6″-Biagpigenin hexamethyleher Apigenin trimethylether (5,7,4′-I-6-II-6 96 trimethoxy-flavone) (I) Apigenin trimethylether (II) 152 MCR360 Volkensiflavone hexamethylether Naringenin triamethylether (5,7,4′-I-3-II-8 95 trimethoxy-flavanone) (I) Apigenin trimethyl ether (II) 153MCR 367 GB-1a hexamethylether Naringenin triamethylether (I) I-3-II-8 87Naringenin trimethyl ether (II) 154 MCR 3983″′-Nitro-C3-O-C4″′-Biflavone Flavone (I) I3′-O-II4′ 61 3′-Nitroflavone(II) 155 MCR 406 3′-8″-Biflavone Flavone (I) I-3′-II-8 49 Flavone (II)156 MCR 400 6-2″′-Biflavone Flavone (I) I-6-II-2′ 9 Flavone (II) 157 MCR407 6-6″-Binaringenin hexamethylether Naringenin trimethylether (I)I-6-II-6 2 Naringenin trimethylether (II) 158 MCR 401 6-2″′-BiapigeninApigenin (I) I-6-II-2′ 1 Apigenin (II) 159 MCR 403 3-3″-Biapigeninhexamethlether Apigenin trimethylether(I) I-3-II-3 0 Apigenintrimethylether (II) 160 MCR402 3-3″-Bi-(7-methoxyflavanone)7-Methoxyflavanone (I) I-3-II-3 0 7-Methoxyflavanone (II) 161 MCR 3998-2″′-Biflavone Flavone (I) I-8-II-2′ 0 Flavone (II) 162 MCR 4047-3″′-Biflavone Flavone (I) I-7-II-3′ 0 Flavone (II) 163 MCR 4054′-4″′-Biflavone Flavone (I) I-4′-II-4′ — Flavone (II) 164 MCR 351Amentoflavone Apigenin (I) I-3′-II-8 0 Apigenin(II) 165 MCR 352Agathisflavone Apigenin (I) I-6-II-8 0 APigenin(II) 166 MCR 353Robustaflavone Apigenin (I) I-3′-II-6 0 APigenin(II) 167 MCR 354Hinokiflavone Apigenin (I) I-4′-O-II-6 0 APigenin(II) 168 MCR 355Rhusflavanone Naringenin (I) I-6-II-8 0 Naringenin (II) 169 MCR 357Succedaneaflavanone Naringenin (I) I-6-II-6 0 Naringenin (II) 170 MCR359 Volkensiflavone Naringenin (I) I-3-II-8 0 Apigenin (II) 171 MCR 363Morelloflavone Naringenin (I) I-3-II-8 0 Luteolin(3′,4′,5,7,-tetrahydroxyflavone) (II) 172 MCR 369 GB-2a Naringenin (I)I-3-II-8 0 Eriodictyol (3′,4′,5,7-tetrahydroxyflavanone) (II) 173 MCR356 Rhusflavanone hexaacetate Naringenin triacetate ((I) I-6-II-8 0Naringenin triacetate (II) 174 MCR 358 Succedaneaflavanone hexaacetateNaringenin triacetate ((I) I-6-II-6 0 Naringenin triacetate (II) 175 MCR364 Morelloflavone heptaacetate Naringenin triacetate (I) I-3-II-8 0Luteolin tetraacetate (3′,4′,5,7-tetraacetoxyflavone) (II) 176 MCR 361Spicataside Naringenin (I) I-3-II-8 0 (Volkensiflavone-7-glucoside)Apigenin-7-glucoside (II) 177 MCR 362 Spicataside acetate Naringenintriacetate (I) I-3-II-8 0 Apigenin-7-glucoside acetate (II) 178 MCR 368Multifloraside Naringenin (I) I-3-II-8 0 (GB-1a glucoside)Naringenin-7-glucoside (II) 179 MCR 370 Xanthochymuside Naringenin (I)I-3-II-8 0 (GB-2a Glucoside) Eriodictyol-7-glucoside (II)

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What I claim:
 1. A composition for treating or preventing amycobacterium infection comprising an effective anti-mycobacteriumeffective amount of a compound of formula i:

wherein R₁-R₉ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁ wherein R₁₀ and R₁₁ independently comprise H alkyl oraryl; COR₁₂ wherein R₁₂ comprises H, OH, O-alkyl, O-aryl or amino;NHCOCH₃; O₂ ⁻; OCOR₁₃ wherein R₁₃ comprises alkyl or aryl; OAc; benzoyl;CONH₂; or NO₂; or a pharmaceutically acceptable derivative or saltthereof and a pharmaceutically acceptable carrier therefor.
 2. Thecomposition of claim 1 wherein, R₁=OH, R₅, R₂=R₄=R₆=R₇=R₈=R₉=H.
 3. Thecomposition of claim 2 wherein R₃ comprises OCH₃, Cl, Br or I.
 4. Thecomposition of claim 1 wherein, R₁=OH, R₂=R₃=R₄=R₆=R₇=R₉=H and R₈=OCH₃.5. The composition of claim 4 wherein R₅ comprises OCH₃ or F.
 6. Thecomposition of claim 1 wherein R₁=OH; R₅=R₃=R₂=R₆=R₇=R₈=R₉=H.
 7. Thecomposition of claim 6 wherein R₄ comprises phenyl, NH₂, Cl, Br or I. 8.The composition of claim 1 wherein R₅=R₂=R₄=R₁=R₆=R₇=R₉=H; R₃=NO₂; andR₈=OCH₃.
 9. The composition of claim 1 wherein R₁=OH;R₅=R₂=R₃=R₄=R₆=R₈=R₉=H.
 10. The composition of claim 9 wherein R₇comprises H, OH, NH₂, Cl or I.
 11. The composition of claim 1 wherein,R₁=R₄=R₃=R₅=R₆=R₉=H; R₂=OH; R₇=OCH₂ ⁻; and R₈=0.
 12. The composition ofclaim 1 wherein, R₁=OH; R₂=R₄=R₆=R₇=R₉=H; R₃=R₈=OCH₃.
 13. Thecomposition of claim 12 wherein R₅ comprises OCH₃ or H.
 14. Thecomposition of claim 1 wherein, R₁=OH; R₅=R₂=R₃=R₄=R₇=R₈=R₉=H.
 15. Thecomposition of claim 14 wherein R₆ comprises OCH₃, Br or I.
 16. Thecomposition of claim 1 wherein R₁=R₂=R₄=R₅=R₆=R₇=R₈=R₉=H; and R₃=NH₂.17. The composition of claim 1 wherein R₁=OH; R₅=R₃=R₂=R₆=R₇=R₉=H; andR₈=OCH₃.
 18. The composition of claim 17 wherein R₄ comprises Cl or Br.19. The composition of claim 1 wherein R₁=OH; andR₅=R₂=R₃=R₄=R₆=R₇=R₉=H.
 20. The composition of claim 19 wherein R₈comprises OCH₃, Cl, Br or I.
 21. The composition of claim 1 whereinR₁=F; R₅=R₂=R₃=R₄=R₆=R₇=R₉=H; and R₈=OCH₃.
 22. The composition of claim1 wherein R₁=OH; R₅=R₂=R₄=R₆=R₇=R₉=H; and R₈=OCH₃.
 23. The compositionof claim 22 wherein R₃ comprises F, Cl or Br.
 24. The composition ofclaim 1 wherein R₁=OH; R₂=F; R₅=R₄=R₃=R₆=R₇=R₉=H; and R₈=OCH₃.
 25. Thecomposition of claim 1 wherein R₁=OH; R₂=Br; and R₅=R₄=R₃=R₆=R₇=R₈=R₉=H.26. The composition of claim 1 wherein R₁=OH; R₅=R₂=R₄=R₇=R₈=R₉=H;R₃=Br; and R₆=NH₂.
 27. The composition of claim 1 wherein R₁=OH;R₅=R₃=R₂=R₇=R₈=R₉=H; R₄=Br; and R₆=NH₂.
 28. The composition of claim 1wherein R₁=R₄=R₃=R₅=R₇=R₈=R₉=H; R₂=NH₂; and R₆=I.
 29. The composition ofclaim 1 wherein R₁=OH; R₅=R₂=R₄=R₆=R₈=R₉=H; R₃=OCH₃; and R₇=I.
 30. Amethod for preventing or treating a mycobacterium infection in a mammalcomprising administering to a mammal in need of anti-mycobacteriumprevention or treatment an effective anti-mycobacterium amount of atleast one compound of formula i:

wherein R₁-R₉ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁ wherein R₁₀ and R₁₁=I independently comprise H alkylor aryl; COR₁₂ wherein R₁₂ comprises H, OH, O-alkyl, O-aryl or amino;NHCOCH₃; O₂ ⁻; OCOR₁₃ wherein R₁₃ comprises alkyl or aryl; OAc; benzoyl;CONH₂; or NO₂; or a pharmaceutically acceptable derivative or saltthereof and a pharmaceutically acceptable carrier therefor.
 31. Themethod of claim 30 wherein, R₁=OH, R₅=R₂=R₄=R₆=R₇=R₈=R₉=H.
 32. Themethod of claim 31 wherein R₃ comprises OCH₃, Cl, Br or I.
 33. Themethod of claim 30 wherein, R₁=OH, R₂=R₃=R₄=R₆=R₇=R₉=H and R₈=OCH₃. 34.The method of claim 33 wherein R₅ comprises OCH₃ or F.
 35. The method ofclaim 30 wherein R₁=OH; R₅=R₃=R₂=R₆=R₇=R₈=R₉=H.
 36. The method of claim35 wherein R₄ comprises phenyl, NH₂, Cl, Br or I.
 37. The method ofclaim 30 wherein R₅=R₂=R₄=R₆=R₇=R₉=H; R₃=NO₂; and R₈=OCH₃.
 38. Themethod of claim 30 wherein R₁=OH; R₅=R₂=R₃=R₄=R₆=R₈=R₉=H.
 39. The methodof claim 38 wherein R₇ comprises H, OH, NH₂, Cl or I.
 40. The method ofclaim 30 wherein, R₁=R₄=R₃=R₅=R₆=R₉=H; R₂=OH; R₇=OCH₂ ⁻; and R₈=O⁻. 41.The method of claim 30 wherein, R₁=OH; R₂=R₄=R₆=R₇=R₉=H; R₃=R₈=OCH₃. 42.The method of claim 41 wherein R₅ comprises OCH₃ or H.
 43. The method ofclaim 30 wherein, R₁=OH; R₅=R₂=R₃=R₄=R₇=R₈=R₉=H.
 44. The method of claim43 wherein R₆ comprises OCH₃, Br or I.
 45. The method of claim 30wherein R₁=R₂=R₄=R₅=R₆=R₇=R₈=R₉=H; and R₃=NH₂.
 46. The method of claim30 wherein R₁=OH; R₅=R₃=R₂=R₆=R₇=R₉=H; and R₈=OCH₃.
 47. The method ofclaim 46 wherein R₄ comprises Cl or Br.
 48. The method of claim 30wherein R₁=OH; and R₅=R₂=R₃=R₄=R₆=R₇=R₉=H.
 49. The method of claim 48wherein R₈ comprises OCH₃, Cl, Br or I.
 50. The method of claim 30wherein R₁=F; R₅=R₂=R₃=R₄=R₆=R₇=R₉=H; and R₈=OCH₃.
 51. The method ofclaim 30 wherein R₁=OH; R₅=R₂=R₄=R₆=R₇=R₉=H; and R₈=OCH₃.
 52. The methodof claim 51 wherein R₃ comprises F, Cl or Br.
 53. The method of claim 30wherein R₁=OH; R₂=F; R₅=R₄=R₃=R₆=R₇=R₉=H; and R₈=OCH₃.
 54. The method ofclaim 30 wherein R₁=OH; R₂=Br; and R₅=R₄=R₃=R₆=R₇=R₈=R₉=H.
 55. Themethod of claim 30 wherein R₁=OH; R₅=R₂=R₄=R₇=R₈=R₉=H; R₃=Br; andR₆=NH₂.
 56. The method of claim 30 wherein R₁=OH; R₅=R₃=R₂=R₇=R₈=R₉=H;R₄=Br; and R₆=NH₂.
 57. The method of claim 30 whereinR₁=R₄=R₃=R₅=R₇=R₈=R₉=H; R₂=NH₂; and R₆=I.
 58. The method of claim 30wherein R₁=OH; R₅=R₂=R₄=R₆=R₈=R₉=H; R₃=OCH₃; and R₇=I.
 59. A compositionfor treating or preventing a mycobacterium infection comprising aneffective anti-mycobacterium effective amount of a compound of formulaii:

wherein R₁=4-fluorophenyl-, 3-hydroxyphenyl-, pyridin-3-yl-,furan-2-yl-, phenanthren-2-yl-, 3-fluorenyl-, pyridin-2-yl-,naphthalen-1-yl-, pyridin-2-yl-, 4-bromo-2-hydroxyphenyl-,pyridin-4-yl-, 2-hydroxy-4-methoxyphenyl-, 4-aminophenyl-,pyridin-4-yl-, 2-hydroxy-5-methoxyphenyl-, 4-methoxyphenyl-,4-methoxyphenyl-, 2-hydroxy-5-chlorophenyl-, 4-aminophenyl-,3-hydroxynaphthalen-2-yl-, furan-2-yl- or pyridin-2-yl-; andR₂=pyridin-3-yl-, phenanthren-9-yl-, phenanthren-9-yl-, phenyl-,2-aminopyridino-3-yl, 2-aminopyridino-3-yl-, pyridin-2-yl-, phenyl-,4-dimethylaminophenyl-, furan-2-yl-, indol-2-yl-, furan-2-yl-,2-aminopyridin-3-yl-, 4-dimethylaminophenyl-, furan-2-yl-,pyridin-4-yl-, pyridin-3-yl-, 2-amino-pyridin-3-yl-,2-aminopyridin-3-yl-, 2-aminopyridin-3-yl-, pyridin-4-yl- or4-methoxyphenyl-; or a pharmaceutically acceptable derivative or saltthereof and a pharmaceutically acceptable carrier therefor.
 60. Thecomposition of claim 59 wherein R₁=4-fluorophenyl- and R₂=pyridin-3-yl-.61. The composition of claim 59 wherein R₁=3-hydroxyphenyl- andR₂=phenanthren-9-yl-.
 62. The composition of claim 59 whereinR₁=pyridin-3-yl- and R₂=phenanthren-9-yl-.
 63. The composition of claim59 wherein R₁=furan-2-yl- and R₂=phenyl-.
 64. The composition of claim59 wherein R₁=phenanthren-2-yl- and R₂=2-aminopyridino-3-yl-.
 65. Thecomposition of claim 59 wherein R₁=3-fluorenyl- andR₂=2-aminopyridino-3-yl-.
 66. The composition of claim 59 whereinR₁=pyridin-2-yl- and R₂=pyridin-2-yl-.
 67. The composition of claim 59wherein R₁=naphthalen-1-yl- and R₂=phenyl-.
 68. The composition of claim59 wherein R₁=pyridin-2-yl- and R₂=4-dimethylaminophenyl-.
 69. Thecomposition of claim 59 wherein R₁=4-bromo-2-hydroxyphenyl- andR₂=furan-2-yl-.
 70. The composition of claim 59 wherein R₁=pyridin-4-yl-and R₂=indol-2-yl-.
 71. The composition of claim 59 whereinR₁=2-hydroxy-4-methoxyphenyl- and R₂=furan-2-yl-.
 72. The composition ofclaim 59 wherein R₁=4-aminophenyl- and R₂=2-aminopyridin-3-yl-.
 73. Thecomposition of claim 59 wherein R₁=pyridin-4-yl- andR₂=4-dimethylaminophenyl-.
 74. A method for preventing or treating amycobacterium infection in a mammal comprising administering to a mammalin need of anti-mycobacterium prevention or treatment an effectiveanti-mycobacterium amount of at least one compound of formula ii:

wherein R₁=4-fluorophenyl-, 3-hydroxyphenyl-, pyridin-3-yl-,furan-2-yl-, phenanthren-2-yl-, 3-fluorenyl-, pyridin-2-yl-,naphthalen-1-yl-, pyridin-2-yl-, 4-bromo-2-hydroxyphenyl-,pyridin-4-yl-, 2-hydroxy-4-methoxyphenyl-, 4-aminophenyl-,pyridin-4-yl-, 2-hydroxy-5-methoxyphenyl-, 4-methoxyphenyl-,4-methoxyphenyl-, 2-hydroxy-5-chlorophenyl-, 4-aminophenyl-,3-hydroxynaphthalen-2-yl-, furan-2-yl- or pyridin-2-yl-; andR₂=pyridin-3-yl-, phenanthren-9-yl-, phenanthren-9-yl-, phenyl-,2-aminopyridino-3-yl, 2-aminopyridino-3-yl-, pyridin-2-yl-, phenyl-,4-dimethylaminophenyl-, furan-2-yl-, indol-2-yl-, furan-2-yl-,2-aminopyridin-3-yl-, 4-dimethylaminophenyl-, furan-2-yl-,pyridin-4-yl-, pyridin-3-yl-, 2-amino-pyridin-3-yl-,2-aminopyridin-3-yl-, 2-aminopyridin-3-yl-, pyridin-4-yl- or4-methoxyphenyl-; or a pharmaceutically acceptable derivative or saltthereof and a pharmaceutically acceptable carrier therefor.
 75. Themethod of claim 74 wherein R₁=4-fluorophenyl- and R₂=pyridin-3-yl-. 76.The method of claim 74 wherein R₁=3-hydroxyphenyl- andR₂=phenanthren-9-yl-.
 77. The method of claim 74 whereinR₁=pyridin-3-yl- and R₂=phenanthren-9-yl-.
 78. The method of claim 74wherein R₁=furan-2-yl- and R₂=phenyl-.
 79. The method of claim 74wherein R₁=phenanthren-2-yl- and R₂=2-aminopyridino-3-yl-.
 80. Themethod of claim 74 wherein R₁=3-fluorenyl- and R₂=2-aminopyridino-3-yl-.81. The method of claim 74 wherein R₁ pyridin-2-yl- and R₂pyridin-2-yl-.
 82. The method of claim 74 wherein R₁=naphthalen-1-yl-and R₂=phenyl-.
 83. The method of claim 74 wherein R₁=pyridin-2-yl- andR₂=4-dimethylaminophenyl-.
 84. The method of claim 74 whereinR₁=4-bromo-2-hydroxyphenyl- and R₂=furan-2-yl-.
 85. The method of claim74 wherein R₁=pyridin-4-yl- and R₂=indol-2-yl-.
 86. The method of claim74 wherein R₁=2-hydroxy-4-methoxyphenyl- and R₂ furan-2-yl-.
 87. Themethod of claim 74 wherein R₁=4-aminophenyl- andR₂=2-aminopyridin-3-yl-.
 88. The method of claim 74 whereinR₁=pyridin-4-yl- and R₂=4-dimethylaminophenyl-.
 89. A composition fortreating or preventing a mycobacterium infection comprising an effectiveanti-mycobacterium effective amount of a compound of formula iii:

wherein R₁-R₈ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁ wherein R₁₀ and R₁₁ independently comprise H alkyl oraryl; COR₁₂ wherein R₁₂ comprises H, OH, O-alkyl, O-aryl or amino;NHCOCH₃; O₂; OCOR₁₃ wherein R₁₃ comprises alkyl or aryl; OAc; benzoyl;CONH₂; or NO₂; or a pharmaceutically acceptable derivative or saltthereof and a pharmaceutically acceptable carrier therefor.
 90. Thecomposition of claim 89 wherein R₁=R₂, R₃=R₄=R₆=R₇=R₈=H.
 91. Thecomposition of claim 90 wherein R₅ comprises Br, Cl or I.
 92. Thecomposition of claim 89 wherein R₁=OH; R₂=R₄=R₅=R₆=R₇=R₈=H.
 93. Thecomposition of claim 92 wherein R₃ comprises Br or I.
 94. Thecomposition of claim 89 wherein R₁=OH; R₂=R₃=R₄=R₅=R₆=R₈=H; and R₇=Br.95. The composition of claim 89 wherein R₁=OH; R₂=R₃=R₅=R₆=R₇=R₈=H; andR₄=Cl.
 96. The composition of claim 89 wherein R₁=R₂=R₃=R₄=R₅=R₆=R₇=H.97. The composition of claim 96 wherein R₈ comprises I, OCH₃, Br, OH orCl.
 98. The composition of claim 89 wherein R₁=OH; R₂=R₃=R₅=R₆=R₇=H; andR₈=OCH₃.
 99. The composition of claim 98 wherein R₄ comprises F or I.100. The composition of claim 89 wherein R₁=OAc; R₂=R₃=R₅=R₆=R₇=H; R₄=F;and R₈=OCH₃.
 101. The composition of claim 89 wherein R₁=OH;R₂=R₄=R₅=R₆=R₇=H; and R₈=OCH₃.
 102. The composition of claim 101 whereinR₃ comprises F, Cl or Br.
 103. The composition of claim 89 whereinR₁=OH; R₂=R₃=R₄=R₅=R₆=R₇=H.
 104. The composition of claim 103 wherein R₈comprises H or OCH₃.
 105. The composition of claim 89 wherein R₁=OCH₃;R₂=R₄=R₅=R₆=R₇=R₈=H; and R₃=Br.
 106. The composition of claim 89 whereinR₁=OH; R₂=R₃=R₄=R₆=R₇=R₈=H; and R₅=F.
 107. The composition of claim 89wherein R₁=R₂=R₃=R₄=R₅=R₆=H; R₇=NO₂; and R₈=Cl.
 108. The composition ofclaim 89 wherein R₁=Br; R₂=R₃=R₄=R₅=R₆=R₇=H.
 109. The composition ofclaim 108 wherein R₈ comprises H of OCH₃.
 110. The composition of claim89 wherein R₁=R₂=R₃=R₄=R₅=R₇, R₈=H.
 111. The composition of claim 110wherein R₆ comprises Br, I or OH.
 112. The composition of claim 89wherein R₁=R₂=R₃=R₄=R₅=R₆=R₈=H; and R₇=I.
 113. The composition of claim89 wherein R₁=R₂=R₃=R₅=R₆=R₇=R₈=H.
 114. The composition of claim 113wherein R₄ comprises I, F or Br.
 115. The composition of claim 89wherein R₁=R₃=R₅=R₆=R₇=H; and R₂=R₄=R₈=OCH₃.
 116. The composition ofclaim 89 wherein R₁=Br; R₂=R₃=R₅=R₆=R₇=H; R₄=OCH₃; and R₈=Cl.
 117. Thecomposition of claim 89 wherein R₁=R₂=R₄=R₅=R₆=R₇=H; and R₈=OCH₃. 118.The composition of claim 117 wherein R₃ comprises I or COOH.
 119. Thecomposition of claim 89 wherein R₁=R₄=benzoyl; R₂=R₃=R₅=R₆=R₇=R₈=H. 120.The composition of claim 89 wherein R₁=R₂=R₄=R₅=R₆=R₇=R₈=H; and R₃=F.121. The composition of claim 89 wherein R₁=OH; R₂=R₃=R₄=R₆=R₇=H; R₅=I;and R₈=OCH₃.
 122. A method for preventing or treating a mycobacteriuminfection in a mammal comprising administering to a mammal in need ofanti-mycobacterium prevention or treatment an effectiveanti-mycobacterium amount of at least one compound of formula iii:

wherein R₁-R₈ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁ wherein R₁₀ and R., independently comprise H allyl oraryl; COR₁₂ wherein R₁₂ comprises H, OH, O-alkyl, O-aryl or amino;NHCOCH₃; O₂; OCOR₁₃ wherein R₁₃ comprises alkyl or aryl; OAc; benzoyl;CONH₂; or NO₂; or a pharmaceutically acceptable derivative or saltthereof and a pharmaceutically acceptable carrier therefor.
 123. Themethod of claim 122 wherein R₁=R₂=R₃=R₄=R₆=R₇=R₈=H.
 124. The method ofclaim 123 wherein R₅ comprises Br, Cl or I.
 125. The method of claim 122wherein R₁=OH; R₂=R₄=R₅=R₆=R₇=R₈=H.
 126. The method of claim 125 whereinR₃ comprises Br or I.
 127. The method of claim 122 wherein R₁=OH;R₂=R₃=R₄=R₅=R₆=R₈=H; and R₇=Br.
 128. The method of claim 122 whereinR₁=OH; R₂=R₃=R₅=R₆=R₇=R₈=H; and R₄=Cl.
 129. The method of claim 122wherein R₁=R₂=R₃=R₄=R₅=R₆=R₇=H.
 130. The method of claim 129 wherein R₈comprises I, OCH₃, Br, OH or Cl.
 131. The method of claim 122 whereinR₁=OH; R₂=R₃=R₅=R₆=R₇=H; and R₈=OCH₃.
 132. The method of claim 131wherein R₄ comprises F or I.
 133. The method of claim 122 whereinR₁=OAc; R₂=R₃=R₅=R₆=R₇=H; R₄=F; and R₈=OCH₃.
 134. The method of claim122 wherein R₁=OH; R₂=R₄=R₅=R₆=R₇=H; and R₈=OCH₃.
 135. The method ofclaim 134 wherein R₃ comprises F, Cl or Br.
 136. The method of claim 122wherein R₁=OH; R₂=R₃=R₄=R₅=R₆=R₇=H.
 137. The method of claim 136 whereinR₈ comprises H or OCH₃.
 138. The method of claim 122 wherein R₁=OCH₃;R₂=R₄=R₅=R₆=R₇=R₈=H; and R₃=Br.
 139. The method of claim 122 whereinR₁=OH; R₂=R₃=R₄=R₆=R₇=R₈=H; and R₅=F.
 140. The method of claim 122wherein R₁=R₂=R₃=R₄=R₅=R₆=H; R₇=NO₂; and R₈=Cl.
 141. The method of claim122 wherein R₁=Br; R₂=R₃=R₄=R₅=R₆=R₇=H.
 142. The method of claim 141wherein R₈ comprises H of OCH₃.
 143. The method of claim 122 whereinR₁=R₂=R₃=R₄=R₅=R₇=R₈=H.
 144. The method of claim 143 wherein R₆comprises Br, I or OH.
 145. The method of claim 122 whereinR₁=R₂=R₃=R₄=R₅=R₆=R₈=H; and R₇=I.
 146. The method of claim 122 whereinR₁=R₂=R₃=R₅=R₆=R₇=R₈=H.
 147. The method of claim 146 wherein R₄comprises I, F or Br.
 148. The method of claim 122 whereinR₁=R₃=R₅=R₆=R₇=H; and R₂=R₄=R₈=OCH₃.
 149. The method of claim 122wherein R₁=Br; R₂=R₃=R₅=R₆=R₇=H; R₄=OCH₃; and R₈=Cl.
 150. The method ofclaim 122 wherein R₁=R₂=R₄=R₅=R₆=R₇=H; and R₈=OCH₃.
 151. The method ofclaim 150 wherein R₃ comprises I or COOH.
 152. The method of claim 122wherein R₁=R₄=benzoyl; R₂=R₃=R₅=R₆=R₇=R₈=H.
 153. The method of claim 122wherein R₁=R₂=R₄=R₅=R₆=R₇, R₈=H; and R₃=F.
 154. The method of claim 122wherein R₁=OH; R₂=R₃=R₄=R₆=R₇=H; R₅=I; and R₈=OCH₃.
 155. A compositionfor treating or preventing a mycobacterium infection comprising aneffective anti-mycobacterium effective amount of a compound selectedfrom the group consisting of 6-6″-biagpigenin hexamethylether,volkensiflavone hexamethylether, GB-1a hexamethylether,3′″-nitro-C3-O-C4′″-biflavone, 3′-8″-biflavone, 6-2′″-biflavone,6-6″-binaringenin hexamethylether and 6-2′″-biapigenin; or derivative orsalt thereof and a pharmaceutically acceptable carrier therefor.
 156. Amethod for preventing or treating a mycobacterium infection in a mammalcomprising administering to a mammal in need of anti-mycobacteriumprevention or treatment an effective anti-mycobacterium amount of atleast one compound selected from the group consisting of6-6″-biagpigenin hexamethylether, volkensiflavone hexamethylether, GB-1ahexamethylether, 3′″-nitro-C3-O-C4′″-biflavone, 3′-8″-biflavone,6-2′″-biflavone, 6-6″-binaringenin hexamethylether and 6-2′″-biapigenin;or derivative or salt thereof and a pharmaceutically acceptable carriertherefor.
 157. A composition for treating or preventing a mycobacteriuminfection comprising an effective anti-mycobacterium effective amount ofa compound of formula iv:

wherein R₁-R₈ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁ wherein R₁₀ and R₁₁ independently comprise H alkyl oraryl; COR₁₂ wherein R₁₂ comprises H, OH, O-alkyl, O-aryl or amino;NHCOCH₃; O₂ ⁻; OCOR₁₃ wherein R₁₃ comprises alkyl or aryl; OAc; benzoyl;CONH₂; or NO₂, or a pharmaceutically acceptable derivative or saltthereof and a pharmaceutically acceptable carrier therefor.
 158. Thecomposition of claim 157 wherein R₁=R₃=R₄=R₆=R₇=R₈=H; R₂=OCH₃; andR₅=Br.
 159. The composition of claim 157 wherein R₁=R₂=R₃=R₄=R₅=R₇=R₈=H;and R₆=Br.
 160. The composition of claim 157 wherein R₁=OH;R₂=R₃=R₄=R₅=R₇=R₈; and R₆=Cl.
 161. The composition of claim 157 whereinR₁=R₂=R₃=R₅=R₆=R₇=R₈=H.
 162. The composition of claim 161 wherein Rcomprises Br, I or F.
 163. The composition of claim 157 whereinR₁=R₂=R₃=R₅=R₆=R₈=H; R₄=OCH₃; and R₇=Cl.
 164. The composition of claim157 wherein R₁=R₂=R₄=R₅=R₆=R₇=R₈=H.
 165. The composition of claim 164wherein R₃ comprises Cl, I or Br.
 166. The composition of claim 157wherein R₁=Br; R₂=R₄=R₆=R₇=R₈=OCH₃; and R₃=R₅=H.
 167. A method forpreventing or treating a mycobacterium infection in a mammal comprisingadministering to a mammal in need of anti-mycobacterium prevention ortreatment an effective anti-mycobacterium amount of at least onecompound of formula iv:

wherein R₁-R₈ are independently comprised of H; OCH₃; EtO; OH;O-alkenyl; phenyl; NH₂; COOH; F; Cl; Br; I; CONH₂; NO₂;NR₁₀R₁₁OCONR₁₀R₁₁ wherein R₁₀ and R₁₁ independently comprise H alkyl oraryl; COR₁₂ wherein R₁₂ comprises H, OH, O-alkyl, O-aryl or amino;NHCOCH₃; O₂ ⁻; OCOR₁₃ wherein R₁₃ comprises alkyl or aryl; OAc; benzoyl;CONH₂; or NO₂; or a pharmaceutically acceptable derivative or saltthereof and a pharmaceutically acceptable carrier therefor.
 168. Themethod of claim 167 wherein R₁=R₃=R₄=R₆=R₇=R₈=H; R₂=OCH₃; and R₅=Br.169. The method of claim 167 wherein R₁=R₂=R₃=R₄=R₅=R₇=R₈=H; and R₆=Br.170. The method of claim 167 wherein R₁=OH; R₂=R₃=R₄=R₅=R₇=R₈; andR₆=Cl.
 171. The method of claim 167 wherein R₁=R₂=R₃=R₅=R₆=R₇=R₈=H. 172.The method of claim 171 wherein R₄ comprises Br, I or F.
 173. The methodof claim 167 wherein R₁=R₂=R₃=R₅=R₆=R₈=H; R₄=OCH₃; and R₇=Cl.
 174. Themethod of claim 167 wherein R₁=R₂=R₄=R₅=R₆=R₇=R₈=H.
 175. The method ofclaim 174 wherein R₃ comprises Cl, I or Br.
 176. The method of claim 167wherein R₁=Br; R₂=R₄=R₆=R₇=R₈=OCH₃; and R₃=R₅=H.